As the U.S. population ages, the prevalence of cancer and its impact on life span, quality of life, and healthcare costs are on the rise. While cancer treatments have greatly improved over the past several decades, they are still inadequate for many forms of cancers, indicating the urgent need for new approaches. A rapidly growing area of research with the potential to greatly improve cancer therapy is the use of immune system as an anti-tumor agent. Currently, several drugs have been developed that target the immune system to treat cancers; however, these drugs are mainly designed to act against late stages of cancers, when cancer cells have already spread to other parts of the body. The limited success of these drugs highlights the need for a fundamentally new approach to cancer treatment using the immune system. The goal of this application is to explore the anti-tumor properties of an immune factor called thymic stromal lymphopoietin (TSLP) that can drive a high degree of immune activation sufficient to prevent cancer formation from pre-cancerous lesions in the first place. This research raises a great opportunity to discover the immune mechanism mediating the anti-tumor effects of TSLP, which can be leveraged in cancer therapy and prevention. To pursue this goal, I will study skin cancer as an ideal cancer model in which the spatial and temporal relationship between inflammation and cancer development can be determined with exceptional precision. Moreover, skin cancer is the most common type of cancer; it is readily identifiable, and amenable to treatment. With the ultimate goal of improving cancer treatment, I plan to study the underlying mechanism of immune activation by TSLP and determine its impact on skin cancer therapy in patients. TSLP is made in the skin and plays a critical role in causing allergic diseases such as eczema. We and others have demonstrated that the skin rash caused by high TSLP levels leads to strong cancer resistance in the affected skin. Our findings are supported by population studies showing resistance to skin cancers among patients with allergic diseases. Importantly, we have found that a short-term increase in TSLP levels leads to a long-lasting resistance to skin cancer with no sign of allergic skin disease in our animal models and patients. This data provides the evidence that immune factors causing inflammatory diseases can be optimized for use in cancer therapy while avoiding their chronic side effects. To determine if TSLP is a good candidate for use in skin cancer immunotherapy, I will study how TSLP causes skin cancer resistance. Specifically, this application will apply mouse models of skin cancer and data from clinical trials to determine (1) the tumor-associated signals that are detected by TSLP-stimulated immune cells to specifically target the tumors, (2) the downstream mechanism by which TSLP-activated immune cells suppress skin cancer development, and (3) the effects of TSLP induction on pre- cancerous skin lesions in humans. The outcome of these studies will help shed light on the mechanism of TSLP action against cancer and promote its development for skin cancer immunotherapy. Considering the emerging importance of the immune system in cancer biology, the understanding of how a pro-inflammatory factor affects cancer development is highly applicable for identifying other immune factors that can be effective in cancer treatment.